Assessment and Grading of Oral Mucositis after Stem Cell Transplantation

Corey Cutler, MD MPH FRCP(C) Dana-Farber Cancer Institute Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts

Stomatitis

A fish hook lodges in my throat. Spittle, kindergarten paste, thickens everything – even vision. Mouth, pocked with sores & blisters, swollen ulcerated tongue. Topside, sandpapered with number 7 coarsest grade. Taste buds, saliva glands, seared. Cool water, corrosive acid now. The tongue rests; teeth become enemies. Coiled steel razored wire atop dentate prison walls. Only moans escape my lips. I cannot eat or speak. Inside a howl festers. Pain lengthens time. – Anita Hart Balter

NEJM. 1990;322:704.

Oral Mucositis

♦Side Effect of Standard Cytotoxic Chemotherapy – Effect on tissues with rapid cell turnover – Bone Marrow - Myelosuppression – Hair Follicles - Alopecia Mouth – GI system - Diarrhea Esophagus - Esophagitis

- Oral mucositis Stoma ch Small Intestine Colon Rectum Anal Can al and Anus

1 Close to 400,000 Patients Per Year Suffer From Mucositis During Cancer Therapy

Breast Colorectal 14% 21% Stem Cell Transplant 4% NHL Head and 5% Neck 15% NSCLC 41%

Source: Mattson Jack Database 2003; NCI; Note: 400,000 patients in the US

Oral Mucositis: The Worst Complication of Myeloablative Transplantation

45 Most Debilitating Side Effects 40

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0 Oral Nausea and Weakness Diarrhea Mucositis Vomiting and Lethargy

Adapted from Bellm LA et al, Support Care Cancer. 2000;8:33-39.

For Every 55 Patients with Severe Mucositis and Myelosuppression…

41 will develop infection …

and 5 will die.

Elting, et al; Cancer 2003

2 Relationship of Mucositis to Outcomes in BMT

Increase in Days: Health Outcome Mucositis vs. No Mucositis Injectable narcotics 4.80 (<0.01) TPN days 5.34 (<0.01) Febrile days 1.59 (<0.02) Significant infection 2.55 (<0.05) Hospital days (autos) 11.02 (<0.01) Hospital days (allos) 6.92 (<0.02)

Pathobiology of Mucositis

Phases II & III Messaging, Phase IV Normal Phase I Signaling, Ulceration Phase V Epithelium Initiation & Amplification (Mucositis) Healing

Radiation

Bacteria

Chemotherapy Submucosa Basal Cell Blood Vessel Inflammatory Fibroblast Cell Epithelial Layer

Clinical Features of Mucositis

♦Erythema ♦Ulceration ♦Pseudomembrane formation ♦Consequences – Pain – Difficulty in swallowing/chewing food – Decreased nutrition – Requirement for IV nutrition – Infectious risk – Breakdown of mucosal barrier – Risk of bacteremia secondary to TPN

3 4 Reasons to ‘Measure’ Mucositis

♦Toxicity description and assessment ♦Medical management ♦Research – Descriptive studies – Intervention studies

Ideal Mucositis Scale

♦Accurately reflects severity and course of objective and subjective clinical changes. ♦Easy to teach and use, with minimal inter- observer variability. ♦Does not require lesion measurement. ♦Sensitive enough to discriminate treatment efficacy. ♦Clinically meaningful and easily interpretable end points for clinicians, patients, and FDA.

Mucositis Research Instruments

♦No uniformity in end points. ♦Wide range of complexity. ♦Provide tight, comparable data, but meaningfulness of end points may be difficult to convey in general clinical settings, ie. How important is a difference between 1.62 vs. 0.77? ♦Major value in phase 2 trials and outcome analyses, but of limited value in phase 3 trials.

5 Mucositis Scale Frequency

WHO NCI CTC Undefined Collaborative study RTOG Bearman Other

Mucositis Scales to be Reviewed

ƒ WHO Oral Toxicity Scale (WHO Score)

ƒ NCI-CTC v3 Mucositis Scale ƒ Clinical Score ƒ Functional/Symptomatic Score

ƒ OMAS

WHO Score ♦ Based on a combination of subjective, objective and functional outcomes:

♦ Subjective– Soreness as described by the patient

♦ Objective – Presence of erythema and ulcerations

♦ Functional– Ability to eat solids, liquids or nothing by mouth

6 WHO Score ♦ Grade 0 – No objective findings, function irrelevant

♦ Grade 1 – Erythema plus pain, function irrelevant

– May include mucosal scalloping with or without erythema or soreness

♦ Grade 2 – Ulceration, ability to eat solids

♦ Grade 3 – Ulceration, ability to eat liquids

♦ Grade 4 – Ulceration, nothing by mouth

WHO Oral Mucositis Scale Severe oral mucositis

Grade 0 1 2 3 4 None Soreness +/– Erythema, Ulcers, extensive Mucositis erythema ulcers erythema to the extent that alimentation is not No ulceration Patients can Patients cannot possible swallow solid swallow solid diet diet

Diet Assessment – Food Definitions ♦Solids – Foods that have to be chewed – Chunky soups, meats, grains, pasta or whole vegetables

♦Liquids – Foods that take the shape of their container – Pureed soups, Jell-O®, pudding, mashed potatoes, baby food, Ensure® or other liquid supplement

♦Nothing Per Os – No eating or drinking, except enough liquid to allow for taking of medications

7 WHO Scale Grading Nuances ƒPain in the absence of objective findings = 0

ƒErythema without pain = 0

ƒUlcers, automatically ≥ 2

ƒExtent or size of ulcers is not a driver

WHO Grading Tips ƒ Grade 1 : If there is an ulcer, it’s not Grade 1 : May include mucosal scalloping with or without erythema or soreness.

ƒ Grade 2 : Can’t be a Grade 2 unless there is an ulcer. Solid diet.

ƒ Grade 3 : Ulcers. Liquid diet. No solids.

ƒ Grade 4 : Mucositis of such severity that eating/drinking is impossible. : PO meds don’t count

WHO Grading Examples

ƒ Subject has a fetanyl patch, large ulceration, 4 no erythema, can eat Jello® and pudding

ƒ Subject is taking an NSAID (within the last 24 hrs) for mouth pain, is now not sore and has 0 erythema

ƒ Subject has no erythema, no soreness, can 2 eat solids and has an ulcer

ƒ Subject has severe erythema, mouth pain and can only tolerate liquids 1

8 NCI-CTC v3 Scoring

♦ Two Components

1. Clinical Score – Objective findings

2. Functional/Symptomatic Score – Functional findings

CTC Clinical Score ♦ 0 = No oral mucositis

♦ 1 = Erythema

♦ 2 = Patchy ulceration or pseudomembrane formation

♦ 3 = Confluent ulceration or pseudomembrane, confluent ulceration occupies >50% of the mucosal surface of the designated anatomic site

♦ 4 = Tissue necrosis

CTC Functional/Symptomatic Score ♦1 = Ability to eat solids

♦2 = Requires liquid diet

♦3 = Not able to tolerate a solid or liquid diet

♦4 = Symptoms associated with life-threatening consequences

♦NOTE: If diet is limited for reasons other than mucositis, the CTC Functional/Symptomatic Score is based on what the subject feels he/she could eat.

9 Anatomic Site-Directed Scoring

♦Inner aspect of upper lip ♦Inner aspect of lower lip ♦Right cheek mucosa ♦Left cheek mucosa ♦Right bottom and side of tongue ♦Left bottom and side of tongue ♦Floor of mouth and frenulum ♦Soft palate

Oral Mucositis Assessment Scale (OMAS)

Sonis et al, Cancer 1999

Correlations Between Peak OMAS Score and Selected Clinical and Economic Outcomes

Febrile days 0.13 Sig infection 0.26* TPN days 0.39* Injectable-narcotic days 0.36* Total hospital days 0.28* Total hospital charges 0.48*

10 How Frequently Should Evaluations Be Done?

♦ Depends on the reason for the assessment. ♦ Mucosal condition in chemotherapy responds relatively acutely. ♦ Consequently, accuracy of assessment tracks well with frequency of evaluation. ♦ Since duration of significant mucositis is the most important driver of untoward outcomes of mucositis, less than daily assessment is risky, especially in clinical trials.

Why Does Mucositis Matter

♦ BMT CTN 0401 – Will intervention make mucositis worse??? ♦ BMT CTN 0402 – Will intervention make mucositis better??? ♦ New interventions exist - Palifermin

0401: Bexxar-BEAM vs BEAM

♦ Autologous transplantation – standard for relapsed non-Hodgkin’s Lymphoma – Usual regimen: High-dose chemotherapy – BEAM or equivalent. – 0401 – Tests hypothesis that the addition of 131I-Tositumomab to high-dose chemotherapy will increase response rate Æ survival

– BUT: Addition of radio-immunotherapy may increase mucositis

11 Pathobiology of Mucositis

Phases II & III Messaging, Phase IV Normal Phase I Signaling, Ulceration Phase V Epithelium Initiation & Amplification (Mucositis) Healing

Radiation

Bacteria

Chemotherapy Submucosa Basal Cell Blood Vessel Inflammatory Fibroblast Cell Epithelial Layer

0402: Effect of Methotrexate Elimination ƒ Retrospective cohort analysis (2001-2003) ƒ Cohorts designated by GVHD prophylaxis: ƒ Sirolimus/Tacrolimus vs. Tacrolimus/Methotrexate ƒ Cy-TBI MRD PBSCT

ƒ Oral Mucositis ƒ Mucositis assessed 2-3x/week by members of the Oral Medicine service ƒ OMAS scale

Other Outcomes ƒ Total Parenteral Nutrition ƒ Total number of days of use recorded

ƒ Narcotic use ƒ Conversion of all narcotics to intravenous mg morphine equivalents (MME) using accepted conversion factors

ƒ Duration of Hospitalization ƒ From day of transplantation to 1st discharge

12 Data Siro / Tacro Tacro / Mtx p Sample Size 30 24 Median Age 42 (19-54) 43 (24-58) 0.46 Male Gender 16 (53%) 11 (46%) 0.78 Malignancy AML/MDS 15 (50%) 16 (67%) CML 7 (23%) 3 (13%) NHL/ALL 8 (27%) 5 (21%) 0.52 Time To ANC > 500 14 (11-17) 15 (11-25) 0.04 Gr II-IV GVHD 3 (10%) 6 (25%) 0.16 Mucositis Assessments 5 6.5 0.36

Mucositis Incidence Duration of Mucositis 60 ST group TM group 30

50 p = 0.0002 p = 0.008 40 15 20 25 20 30 10 Mucositis (days) 10 Mucositis Incidence (%) Duration of Ulcerative 05 0

0-1 2-3 4-5 ST group TM group Peak Mucositis Score

TPN usage Days of TPN required

ST group 80 TM group

p = 0.08 p = 0.005 30 60 40 Duration of TPN Usage Duration of Patients Requiring TPN(%) Patients Requiring 01020 020

ST group TM group

13 Narcotic Utilization

p = 0.08 p = NS p = NS p = NS 1400 100 1200

80 1000

60 800

600 MME

MME/day MME/day 40

Narcotic Days 400

MME/ narcotic day narcotic MME/ 20 200

0 0 Narcotic Days Total MME MME/Day MME/Narcotic Day MME = mg Morphine Equivalents

Duration of Hospitalization 70 ) * p = 0.07 60

*

* * 20 30 40 50 Duration of HospitalizationDuration of (days

ST group TM group

Methotrexate Conclusions

♦ GVHD prophylaxis with Sirolimus-Tacrolimus is associated with less oral mucositis than with a Methotrexate-containing regimen

♦ Patients who do not receive Methotrexate require less TPN and less narcotics

♦ Hospitalization duration is shortened in patients not treated with Methotrexate

♦ The improved mucositis outcomes with non-Methotrexate containing regimens may be associated with substantial cost savings.

14 Prevention of Oral Mucositis

♦“Many are called, but few are chosen” – Multiple agents failed in randomized trials; – Until recently, no standard ♦Palifermin ♦Velafermin

Palifermin

♦ The mouth is covered in specialized epithelium called keratinocytes ♦ Palifermin is a recombinant N-terminal truncated version of Keratinocyte Growth Factor (KGF) with same biological activity but increased stability ♦ KGF is a 28kD, heparin-binding member of the fibroblast growth factor family ♦ Ameliorates mucositis in murine model

Palifermin-Induced Thickening of Normal Tongue Mucosa

Ventral surface of rodent tongue mucosa in absence or presence of palifermin (rHuKGF) 5 mg/kg/day for 3 days

15 Palifermin

♦Phase I (Meropol et al, JCO 1993): – Doses of 80 ug /kg x 3 d appeared safe ♦Phase II (Sonis et al, Cancer 1995) – Etoposide, Cytarabine, Melphalan preparative regimen – Reduced mucositis and weight loss ♦Phase III (Spielberger et al, NEJM 2004) – Palifermin vs. placebo in XRT-containing preparative regimen for autologous transplant

Palifermin vs. Placebo - Design

♦Inclusion – > 18 yo – KPS > 70% – Autotransplant planned for heme malignancy ♦Treatment – Etoposide/Cytoxan/TBI preparative regimen – Palifermin @ 60 ug/kg x 3d iv prior to XRT – Palifermin @ 60 ug/kg x 3d iv d0, 1, 2 – Double blind – G-CSF given from d0 to recovery

Palifermin vs. Placebo - Endpoints

♦Mucositis assessment daily, multiple scales – WHO – RTOG – WCCNR ♦Patient-reported outcomes – Sore throat – ADL participation ♦Narcotic use ♦TPN use ♦Primary endpoint: duration of WHO gr3/4 mucositis

16 Palifermin vs. Placebo - Patients

Spielberger, R. et al. N Engl J Med 2004;351:2590-2598

Palifermin vs. Placebo - Results

98% 9d 63% 3d

Spielberger, R. et al. N Engl J Med 2004;351:2590-2598

Palifermin vs. Placebo – Patient-Reported Outcomes

Spielberger, R. et al. N Engl J Med 2004;351:2590-2598

17 Palifermin vs. Placebo - Results

♦Lower dose of opioids administered (morphine equivalents): 212 vs. 535 mg ♦Lower duration of opioid administration: 7 vs. 11d ♦Lower incidence of febrile neutropenia: 75 vs. 92% ♦Lower incidence of blood-borne infections: 15 vs. 25% ♦Lower incidence of TPN use : 31 vs. 55%

Palifermin vs. Placebo - Safety

♦Rarely discontinued ♦Most events with > 5% frequency in palifermin group (and not in placebo group) were due to effect of drug on skin and oral epithelium ♦SAE: Rash; Hypotension ♦Deaths: 1 in each group ♦12 month PFS is similar in both groups ♦No excess of cancer deaths in either group (ie KGF does not protect tumors)

Palifermin vs. Placebo - Conclusions

♦Palifermin was effective in reducing the incidence and duration of severe and life-threatening mucositis ♦Reduction in opioid and TPN use probably beneficial for pts

♦Other Questions: – Role in Allo transplant – not effective as GVHD prophylaxis

18 Velafermin

♦Recombinant Human Fibroblast-Growth Factor-20 ♦Promotes Epithelial and Mesenchymal cell proliferation – prevents mucositis in animal models ♦Being tested in Ph II trials in people undergoing autologous transplantation

Velafermin Trial

Schuster et al, ASCO 2006

Velafermin – Patient Population

Schuster et al, ASCO 2006

19 Velafermin - Outcomes

* Non-Dose Dependent Pharmacology suggested in animal studies

Schuster et al, ASCO 2006

Velafermin

♦Primary Endpoint not met in this trial – ♦Safety established ♦Further studies planned at optimal dose

Summary

♦ Mucositis - An important complication of myeloablative transplantation ♦ Scoring – Important for research and patient care ♦ New agents may change incidence and severity ♦ New agents may prevent mucositis – need to be tested further

20 ♦ Acknowledgements – Nathaniel Treister, DMD – Stephen Sonis, DMD – Richard Stone, MD

21